“A Chimeric Human-Mouse Model of Sjögren's Syndrome”
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Transcript of “A Chimeric Human-Mouse Model of Sjögren's Syndrome”
Introduction Sjögren’s syndrome (SjS) is one of the most common autoimmune diseases,
affecting 4 million Americans
Although systemic inflammatory responses are observed, this autoimmune disease mainly affects the salivary and lacrimal glands
The pathogenic mechanisms remain elusive and an ideal model for early drug discovery is not yet available
The pathogenesis of SjS is currently thought to involve many factors
research concerning SjS development, progression, and molecular-based therapeutics requires in vivo animal models
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Background Mouse models do not translate efficaciously into human patients
Ethical and technical constraints limit such studies in human systems humanized mice, or human-mouse chimeras
The transgenic mouse strain NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ is more commonly known as NOD scid gamma (NSG)
Cannot produce T-cells, B-cells, or functional NK cells due to several targeted mutations.
Successful human engraftment using 10-fold fewer human cells than the preceding humanized mouse strains
NSG chimeras display no symptoms of graft versus host disease for at least 30 days
allowing a 4-5 week window for investigation
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Objective
NSG mice have not been used extensively in the investigation
of autoimmune disorders
New SjS models can be used in the discovery of therapeutic
alternatives to the current management of SjS
Non-specific and largely supportive
We take advantage of the NSG model to engraft and study SjS
pathology in vivo.
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Experimental set-up
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Blood-flow cytometry
Histology
Serum- cytokines
IHC
28 days
Healthy
or
SjS
IP
5 X 10^6 cells
Summary Robust CD4+ T-cell infiltration in the salivary and lacrimalglands at 28 days
Significantly higher levels of IFN-g, IL-6, IL-10, IL-17, andTNF-α.
Both IFN-g and IL-10 previously shown to be elevated inperipheral blood T-cells of SjS patients
Histopathology and immunohistochemistry recapitulate what is seen in SjS patients Useful for the study of molecular-based therapies to treat
and prevent disease pathology14
Conclusions
Immunohistochemical data on lacrimal glands in SjS is lacking due to the inaccessibility of this tissue in humans for biopsy
Novel chimeric mouse model of SjS that will allow the in vivo study of autoimmune-mediated inflammation on human immune cells
Opens new avenues to study disease progression and therapeutic intervention
Future work: investigate molecular-based targets to prevent target organ inflammation in SjS and other autoimmune disorders
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Acknowledgements
Lai-Chu Wu, PhD
William Willis, PhD
Benjamin Kaffenberger, MD
Alexandra Friedman
Michael Bruss
Giancarlo Valiente
Mark Gardner
Amanda Kibler
The Ohio State University Wexner Medical Center, Columbus, OH
Department of Internal Medicine
Division of Rheumatology and Immunology
Department of Microbial Infection
and Immunity
Center for Microbial Interface Biology
The Ohio State University
College of Veterinary Medicine
Larry S. Schlesinger, MD
Murugesan V.S. Rajaram, PhD
Brad Bolon, DVM, MS, PhD
Wael Jarjour, MD
Department of Internal Medicine
Division of Rheumatology and Immunology